Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
  • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
  • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

• the object of the present invention is a process for preparing a clodronate preparation by dry granulation, where the crystalline phase of the clodronate raw material used is the stable and easy-to-handle tetrahydrate of the clodronic acid disodium salt (CH 2 Cl 2 O 6 P 2 Na 2 4H 2 O), with a definite crystal form.
• Clodronate or the disodium salt of (dichloromethylene) bisphosphonic acid, tetrahydrate is useful for instance in the treatment and prophylaxis of disorders of the calcium metabolism, such as bone resorption, hypercalcaemia and osteoporosis.
• disorders of the calcium metabolism such as bone resorption, hypercalcaemia and osteoporosis.
• clodronate Based on its ability to form a strong complex with a Ca 2+ -ion, clodronate removes excessive calcium from the circulation, prevents calcium phosphate from dissolving from the bone and/or acts via cell-mediated mechanisms.
• a problem with clodronate preparations has therefore been how to achieve a sufficiently high amount and concentration of the active agent in a capsule or tablet, without having to use capsule or tablet sizes which are unpleasantly large for the patient.
• the clodronate powder thus obtained is, however, inaccurate as regards its composition and obviously difficult to handle (sticky, very poor flow properties). It is thus extremely difficult in practice to mix it with other substances used in the preparation, as well as to further process it, wherefore for instance a relatively large amount of gliding agents is needed. From the unhomogenous raw powder an unhomogenous and poorly flowing product mass is then obtained, which affects also the accuracy of dosing of the final medicament.
• the bulk volume of the clodronate raw material generally varies a great deal between different batches of preparation, due to the difficultly controlled crystallization process in the preparation of the raw material, where the four crystal waters must have time to take their positions in the crystal lattice in order to obtain a uniform and non-caking composition but where, on the other hand, a too slow crystallization leads to an unsuitably large crystal volume.
• this has the effect that the amount of granulating liquid has to be varied from one granulation batch to the next, depending on the quality of the raw clodronate, in order to obtain, as the end product, granules with the same bulk volume.
• the wet granulation process is thus an extremely difficult and laborious process and the final result is often, however, unforeseeably inaccurate.
• the wet granulation process is always connected with time-consuming and expensive drying of the granules.
• a second balancing regarding the four necessary crystal waters is required in the drying stage of the wet granulation process.
• Dry granulation is thus an effective way to minimize the bulk volume of the clodronate raw material. This is particularly of advantage when clodronate is administered in capsule form, whereby the size of the capsule may be chosen as small as possible.
• the object of the present invention is thus a process for preparing a clodronate preparation, which process comprises the following steps:
• clodronate is crystallized as disodium clodronate tetrahydrate from an aqueous solution of disodium clodronate,
• the resulting disodium clodronate tetrahydrate is dry granulated by compressing in such a way that the crystal structure of the disodium clodronate tetrahydrate is preserved, and thereafter by crumbling and screening the mass to granules of a suitable size,
• the dry granulated disodium clodronate tetrahydrate is optionally mixed with suitable excipients, such as filling agents and gliding agents and, if necessary, disintegrants.
• Crystallization may be carried out by adding, in a controlled manner, to an aqueous solution of disodium clodronate an organic solvent which is fully or partly water-soluble but in which disodium clodronate is poorly soluble, and by gradually lowering the temperature while stirring, whereby the disodium clodronate crystallizes as the tetrahydrate.
• water-soluble organic solvents for example, a water-soluble lower alcohol, such as methanol or ethanol, n-propanol, isopropanol, t-butanol, glycol, glycol ethers, tetrahydrofuran, dioxane, acetone, especially ethanol, methanol, monomethyl and ethyl ethers of glycol, tetrahydrofuran, dioxane or acetone, come into question, and ethanol is especially preferred.
• a water-soluble lower alcohol such as methanol or ethanol, n-propanol, isopropanol, t-butanol, glycol, glycol ethers, tetrahydrofuran, dioxane, acetone, especially ethanol, methanol, monomethyl and ethyl ethers of glycol, tetrahydrofuran, dioxane or acetone, come into question, and ethanol is especially preferred.
• the starting temperature is higher than room temperature, e.g. 30°-120° C., preferably 60°-100° C., especially 70°-90° C. and most preferably about 80° C.
• the rate and manner of adding the solvent are to be such that clodronate does not precipitate prematurely or untimely without its crystal water molecules.
• the final temperature is 0°-20° C., preferably about 15° C., to which it has been lowered from the starting temperature of 80° C.
• Temperature may be lowered continuously or stepwise, e.g. by keeping the temperature for a while at about 40° C.
• disodium clodronate tetrahydrate is obtained as easily processable fine flakes or needles.
• the size of the crystals can be adjusted by changing the rate of addition of the organic solvent component and/or the rate of lowering the temperature.
• Crystallization may also be carried out by evaporating an aqueous solution of disodium clodronate slowly so that the proportion of water is reduced, in the presence or absence of a water-soluble or partly water-soluble organic solvent, such as mentioned above, and also in the presence of an organic solvent which is poorly soluble in water, in a two-phase system at a temperature of at least about 20° C. but no more than about 100° C., preferably 40°-70° C., while the solution is stirred. If desired, the evaporation may be performed under reduced pressure, whereby the temperature may correspondingly be lower.
• a water-soluble organic solvent for example, a water-soluble lower alcohol, such as ethanol, n-propanol, isopropanol, t-butanol, glycol or glycol ether may be used.
• an organic solvent which is poorly or partly water-soluble for example methylene chloride, chloroform, methyl ethyl ketone, ethyl acetate, butanols, such as 1- and isobutanol, or a mixture of these and those mentioned above come into question, especially methylene chloride, chloroform, 1-butanol, glycol or a monomethyl or monoethyl ether of glycol.
• Possible residues of organic solvent may be removed e.g. by washing with ethanol and drying at a temperature, at which the crystalline tetrahydrate does not yet liberate its one crystal water which is most easily released ( ⁇ 50° C.). By crystallizing this way, disodium clodronate tetrahydrate is obtained as a fine crystalline powder with good handling properties.
• disodium clodronate with four crystal waters as the raw material of a clodronate preparation, which crystal form obtained in the very manner as described above, as a flake, needle and powder, is stable and easy to handle.
• the equilibrium is disturbed for example by removing or adding crystal waters, i.e. by heating or moistening, the drug raw material becomes sticky or cakes and is thus difficult to handle.
• the first of the four crystal waters is split off relatively easily and rapidly at a temperature of >50° C., it is of vital importance to keep the conditions in the different stages of the manufacturing process of the pharmaceutical preparation such that the tetrahydrate structure is preserved.
• Disodium clodronate tetrahydrate which has been crystallized as described above, may be characterized by powder X-ray diffraction and single crystal X-ray diffraction.
• the crystal structures measured fully correspond to the published one (Nardelli and Pelizzi, Inorg. Chim. Acta 80 (1983) 289), and thus the structure of the clodronate used in the dry granulation of the invention and of the clodronate crystallized for this purpose according to the invention is correct.
• disodium clodronate crystallized as described above is dry granulated under controlled conditions, the structure of disodium clodronate tetrahydrate is preserved and dense, easy-to-handle granules of uniform quality are formed.
• the granulation is performed as a dry granulation whereby disodium clodronate tetrahydrate is compressed, preferably between rollers, to a thin sheet or mass which is further crumbled and screened to granules of a suitable size.
• the dry granulation is performed under such temperature and pressure conditions that the crystal structure of the disodium clodronate tetrahydrate is preserved.
• the compression pressure is 30-90 bar, preferably 40-75 bar and most preferably about 50-65 bar.
• the speed of the rollers during compression is 8-16, preferably 8 rpm. Compression is performed at a temperature, which is close to room temperature, however, not higher than about 40°-50° C., preferably at 20°-30° C.
• the granules obtained by dry granulation can, if desired, be mixed with suitable excipients, such as filling agents and gliding agents/lubricants and, if necessary, disintegrants. According to the invention, the amount of excipients can be kept low, due to the good handling characteristics of the clodronate granule powder obtained from the dry granulation process.
• excipients optionally used in preparations of solid clodronate and mixtures thereof are such that do not bind or release water, in order not to disturb its tetrahydrate structure.
• the filling agents (weight balancing agents) to be used may be for example lactose, especially a-lactose monohydrate, microcrystalline cellulose, starch or its derivatives, mannitol, glucose, saccharose, or a mixture of two or more filling agents.
• a preferred filling agent according to the invention is ⁇ -lactose monohydrate, which is used in an amount necessary to adjust the amount of disodium clodronate in the preparation to the desired level.
• the amount of filling agent is thus about 0-20% by weight, usually about 2-12% by weight, based on the weight of the final preparation.
• flavouring and sweetening agents such as natural or artificial flavourings and sweeteners, in the amounts needed.
• gliding agents the conventional gliding agents and lubricants known in the art can be used, such as stearic acid or its salts (Mg--, Ca--), talc, starch, colloidal silica or a mixture of two more gliding agents, preferably stearates and/or talc.
• the amount of gliding agent can and should be kept low, as for example the optional calcium or magnesium containing agents in the preparation bind clodronate by forming a complex therewith, whereby the absorption of the drug is decreased.
• the amount of gliding agents can be substantially lowered or its use can even be totally abandoned, whereby the amount of the active agent in the preparation can be kept high and its absorption in the organism does not decrease.
• the amount of gliding agent can be for example 0-10% by weight, especially 2-6% by weight, based on the weight of the final preparation.
• disintegrants can be added to the preparation.
• disintegrants may be used for example about 0-3% by weight, especially about 0.5-1% by weight, based on the weight of the final preparation.
• the preparation can be coated with as such known film forming agents, which dissolve at the desired pH, such as for example with shellac, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate or various acryl and methacryl acid derivatives.
• film forming agents are known to a person skilled in the art and are commercially available.
• the obtained mixture is suitable for administration as a number of different formulations formed from crystal phase clodronate.
• it can for example be filled in capsules, compressed into tablets or used as granules or a powder according to methods generally known in the art, and further coated, if desired.
• capsules and tablets the size of which can be kept small due to the methods of the invention.
• a drug delivery form prepared by the process according to the invention preferably comprises 60-80% by weight of anhydrous disodium clodronate.
• it contains 65-75% by weight of anhydrous disodium clodronate (corresponds to about 81-94% of the tetrahydrate form), about 2-12% by weight of a filler, for example lactose, about 2-6% by weight of a gliding agent, for example talc or calcium stearate, and about 0-1%, especially 0.5-1% by weight of a disintegrant, based on the weight of the final preparation.
• compositions prepared according to the invention are (% by weight):
• the resulting disodium clodronate tetrahydrate was dry granulated by compressing in a roller compactor under a pressure of about 60 bar at room temperature (20°-25° C.) until a suitable bulk density was achieved.
• the desired bulk density was typically obtained with a granule size over 0.5 mm.
• Capsules were prepared with the following composition per capsule:
• the disodium clodronate concentration (as anhydrous) of the composition is thus 70.2% by weight.
• Granules of dry granulated disodium clodronate tetrahydrate were mixed with calcium stearate, talc, anhydrous silica and lactose The mixture was filled into capsules (size no. 1).
• Disodium clodronate tetrahydrate was dry granulated as described above.
• Capsules were prepared with the following composition per capsule:
• Disodium clodronate tetrahydrate was dry granulated as described above.
• Capsules were prepared with the following composition per capsule:
• Disodium clodronate tetrahydrate was dry granulated as described above. Tablets were prepared with the following composition per tablet:
• Dry granulated disodium clodronate tetrahydrate, sodium croscarmellose, anhydrous silica and microcrystalline cellulose were mixed into a homogenous mixture. Thereafter magnesium stearate was added to the mixture and stirred.
• the obtained powder mixture was tabletted using punches of a suitable size, for example round, concave punches with a diameter of 12 mm, to a suitable strength, for example to 7-9 kg.
• Disodium clodronate tetrahydrate was dry granulated as described above. Dosage powders were prepared to be taken as such or to be mixed with water. The composition of the powder per sachet was as follows:
• Dry granulated disodium clodronate tetrahydrate, aspartame, flavouring and mannitol were mixed into a homogenous mixture. Then magnesium stearate was added and mixed. The powder mixture was filled into sachets of a suitable size.
• Disodium clodronate tetrahydrate was dry granulated as described above.
• the granules were coated with an enteric film in an air suspension apparatus.
• the composition of the coating :
• coated granules may be filled into capsule shells or suitable sachets.

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• 1993
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• 1994
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  • 1994-11-11 DK DK95900155T patent/DK0727983T3/da active
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